Abstract
The neuroprotective effect of mitochondrial isocitrate dehydrogenase (IDPm), an enzyme involved in the reduction of NADP+ to NADPH and the supply of glutathione (GSH) in mitochondria, was examined using SH-SY5Y cells overexpressing IDPm (S1). S1 cells showed higher NADPH and GSH levels than vector transfectant (V) cells and were more resistant to staurosporine-induced cell death than controls. Staurosporine-induced cytochrome c release, caspase-3 activation, and production of reactive oxygen species (ROS) were significantly attenuated in S1 cells as compared to V cells and reduced by anti-oxidants, trolox and GSH-ethyl ester (GSH-EE). Staurosporine-induced the release of Mcl-1 from mitochondria that formed a complex with Bim. Mcl-1 was then cleaved to a shortened form in a caspase-3 dependent manner; its release was attenuated far more in S1 than in V cells after staurosporine treatment. Finally, the staurosporine-induced decrease in mitochondrial membrane potential (Δψm) was correlated with the time of mitochondrial Mcl-1 release; the loss of Δψm was attenuated significantly in S1 cells as compared to that in V cells. These results suggest that the neuroprotective effect of IDPm may result from increases in NADPH and GSH levels in the mitochondria. This, in turn, inhibits mitochondrial ROS production after cytochrome c release, which seems to be mediated through Mcl-1 release.
| Original language | English |
|---|---|
| Pages (from-to) | 139-152 |
| Number of pages | 14 |
| Journal | Journal of Neuroscience Research |
| Volume | 85 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2007 Jan |
Bibliographical note
Funding Information:We thank Sylvia Doan, David Twa, James T. Harper, Magne Osteras, Loïc Baerlocher and Lisa Bowers for help with sequencing, genome assembly and handling of microsporidian material. This work was supported by a Canadian Institutes for Health Research grant to P.J.K. (MOP-42517) and funding from the USA National Institutes of Health (RR00164 and AI071778) to E.S.D. P.J.K. is a Fellow of the Canadian Institute for Advanced Research (CIFAR) and a Senior Scholar of the Michael Smith Foundation for Health Research. N.C. is a scholar of the CIFAR and, at the time of the study, a Senior Postdoctoral Fellow of the Swiss National Science Foundation (PA00P3_124166). J.F.P. is the recipient of the Fonds Québécois de la Recherche sur la Nature et les Technologies (FQRNT)/Génome Québec Louis-Berlinguet Postdoctoral Fellowship.
All Science Journal Classification (ASJC) codes
- Cellular and Molecular Neuroscience